Hepatitis C is a global epidemic disease. At present, there are more than 200 million patients with hepatitis C, including tens of millions patients in China. NS5B inhibitors, which are polymerase inhibitors, can interfere with virus replication by binding with NS5B RNA-dependent RNA polymerase. Such drugs are classified into nucleoside inhibitors and non-nucleoside inhibitors. The nucleoside inhibitor, also known as active site inhibitors, can be intercalated into the RNA strand in the disguise of natural substrates of the polymerase to interrupt the replication of the RNA. Therefore, such drugs can combat HCV infections of all genotypes, and the antibiotic resistance of the virus thereto is very low. Among them, 2-fluoro-2-methyldeoxyuridine triphosphoric acid is an intracellular potent NS5B inhibitor, but cannot be transported to the lesion in vivo. Thus, a prodrug of its inactive form 2-fluoro-2-methyldeoxyuridine monophosphate can be used, which may be metabolized into the 2-fluoro-2-methyldeoxyuridine monophosphate and then activated into 2-fluoro-2-methyldeoxyuridine triphosphoric acid in vivo, thereby inhibiting the NS5B and playing an anti-HCV effect.
Currently, a strategy of adding a masking group to a phosphate group to form a prodrug is adopted, wherein a chemical compound containing one masking group forming a phosphoramide structure with the phosphate group and the other group forming a phosphate ester with the phosphate group has been proven to have the liver targeting effect. Ester-forming groups include various aromatic rings and heteroaromatic rings used in tenofovir prodrugs, especially phenol esters (CN201310041647.4, WO02082841), but the synthesis and bioactivity of an ester-forming group as a prodrug of 2-fluoro-2-methyldeoxyuridine monophosphate of a relatively non-toxic benzyl, natural alcohol, saccharide, or vitamin.
The present invention aims to provide a novel uridine monophosphoramide prodrug compound, a preparation method thereof, and uses thereof in the preparation of a drug for the treatment of viral infectious diseases so as to simultaneously improve the liver targeting ability and the bioavailability of the drug, thus improving the therapeutic effect of the drug and reducing the dosage and the toxicity of the drug.